Pulmonary hypertension summarizes various conditions in which the blood pressure in the pulmonary circulation is significantly elevated. By definition, pulmonary hypertension is diagnosed when the mean pulmonary arterial pressure (mPAP) exceeds 25 mmHg as measured by right-heart catheterization. Pulmonary arterial hypertension (PAH) is a syndrome in which pulmonary arterial obstruction increases pulmonary vascular resistance, which leads to right ventricular (RV) failure. Pulmonary hypertension is a serious illness that becomes progressively worse and is sometimes fatal. There are 5 categories of pulmonary hypertension (PH) in the latest World Health Organization classification: (1) PAH; (2) PH associated with left-sided heart disease; (3) PH associated with lung disease/hypoxia; (4) thromboembolic PH; and (5) miscellaneous. In all groups, the average pressure in the pulmonary arteries is higher than 25 mmHg at rest or 30 mmHg during physical activity, with a mean pulmonary-capillary wedge pressure and left ventricular end-diastolic pressure of less than 15 mmHg. The pressure in normal pulmonary arteries is 8-20 mmHg at rest. (The mmHg is millimeters of mercury—the units used to measure blood pressure.). There is no cure for PAH but treatments currently available can help lessen symptoms and improve your quality of life. Treatment of PAH involves the use of prostanoids (given intravenously, by inhalation, subcutaneously, or orally), endothelin receptor blockers, and PDE5 inhibitors. PAH treatments remain expensive and/or difficult to deliver and are more palliative than curative.
Although many advances have been made in recent years, especially pertaining to the molecular genetics and cell biology of idiopathic pulmonary hypertension, the pathogenesis of most forms of PAH is still not fully understood. Serotonin or 5-Hydroxytryptamine (5-HT) has been reported to play a key role in both proliferative and functional components of PAH pathogenesis (Esteve et al., Cell Biochem Biophys 2007; Dempsie and MacLean, Brit j Pharmacol 2008; Dumitrascu et al., Eur Respir J 2011). Serotonin is a vasoconstrictor that promotes smooth-muscle cell hypertrophy and hyperplasia. Elevated levels of plasma serotonin and reduced content of serotonin in platelets have been found in idiopathic pulmonary hypertension. A platelet defect that defect that results in a reduced uptake of serotonin has been associated with PAH. Recently, mutations in the serotonin transporter (5-HTT), serotonin 2A receptor (5-HT2A) and serotonin receptor (5-HT2B) have been implicated in PAH (Eddahibi et al., J Clin Invest 2001). The 5-HT2A receptor present in human pulmonary arteries mediates vasoconstriction of the systemic circulation. Antagonism of the 5-HT2A receptor inhibits monocrotoline induced PAH in mice (Hironaka et al., Cardiovasc Res 2003), and also inhibits serotonin-induced pulmonary vasoconstriction in vessels from both normoxic and hypoxic rats (Morcroft et al., J Pharmacol Exp Ther 2005; Cogolludo et al., Circ Res 2006). Moreover, the 5-HT2A receptor mediates serotonin-induced proliferation of rat pulmonary arterial fibroblasts (Welsh et al., Am J Respir Crit Care Med 2004). 5-HT2B receptor is expressed in pulmonary endothelial and smooth muscle cells and stimulate calcium release in human endothelial cells from the pulmonary artery ((Esteve et al., Cell Biochem Biophys 2007). In the chronic hypoxic mouse model of pulmonary hypertension, researchers demonstrated that 5-HT2B receptor is involved in the development of pulmonary hypertension by mediating chronic hypoxic responses in wild-type mice compared with the complete absence of pulmonary hypertension and vascular remodeling in 5-HT2B receptor deficient mice (Launay et al., Nat Med 2002). Recently, PRX-08066, a selective 5-HT2B receptor antagonist (Provasnik et al., J Pharmacol Exp Ther 2010), and terguride, an antagonist of both 5-HT2A and 5-HTB receptors (Dumitrascu et al., Eur Respir 2011), were shown to prevent the development of PAH in rat monocrotoline (MCT) model. The pathogenesis of pulmonary hypertension is characterized by three major processes including vasoconstriction, vascular remodeling and microthrombotic events. In addition, accumulating evidence point to a cytokine driven inflammatory process as a major contributor to the development of pulmonary hypertension.
There is a pressing need for less expensive and more effective therapies for treating PAH.